ABSTRACT
Two phase-III, double-blind, randomized clinical trials of remdesivir plus SOC (standard of care) versus placebo plus SOC have been conducted in Wuhan hospitals by Chinese investigators during the urgent COVID-19 epidemic [ClincalTrials.gov NCT04257656 and NCT04252664]. These trials have been highly anticipated worldwide. We expect investigators of the trials will soon report the clinical and laboratory findings from the medical perspective. This manuscript provides documentary style information on the process of monitoring key data and making recommendations to the sponsor and investigators based on analytical insights when dealing with the emergent situation from the statistical viewpoint. Having monitored data sequentially from 237 patients, we comment on the strength and weakness of the study design and suggest the treatment effect of remdesivir on severe COVID-19 cases. Our experience with using the Dynamic Data Monitoring (DDM) tool has demonstrated its efficiency and reliability in supporting DSMB's instantaneous review of essential data during the emergent situation. DDM, when used properly by disciplined statisticians, has shown its capability of exploring the trial data flexibly and, in the meantime, protecting the trial's scientific integrity.
Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Antiviral Agents/therapeutic use , Betacoronavirus/drug effects , Clinical Trials, Phase III as Topic , Coronavirus Infections/drug therapy , Data Accuracy , Pneumonia, Viral/drug therapy , Randomized Controlled Trials as Topic , Research Design , Adenosine Monophosphate/adverse effects , Adenosine Monophosphate/therapeutic use , Alanine/adverse effects , Alanine/therapeutic use , Antiviral Agents/adverse effects , Betacoronavirus/pathogenicity , COVID-19 , China , Clinical Trials Data Monitoring Committees , Coronavirus Infections/diagnosis , Coronavirus Infections/virology , Host Microbial Interactions , Humans , Pandemics , Pneumonia, Viral/diagnosis , Pneumonia, Viral/virology , SARS-CoV-2 , Time Factors , Treatment Outcome , COVID-19 Drug TreatmentABSTRACT
Introduction: The first clinical trial on remdesivir for treatment of severe COVID-19 conducted in China was terminated prematurely due to limited patient enrollment, which rendered the findings inconclusive. We re-analyzed the efficacy with a statistically more powerful and clinically meaningful method based on published data using the 6-point ordinal scale of patient's disease severity. Methods: We defined response as patient's point reached, either 2 (hospitalized, no requirement for supplementary oxygen therapy) or 1 (discharged or met discharge criterion), and then analyzed with logistic regression with baseline score, day of assessment, treatment group, baseline by treatment interaction, and day by treatment interaction as covariates. The binary endpoint was supported by the recent FDA's guidance on COVID-19. Results: Eighty-two percent (82%) of the patients were in the disease severity point=3 (hospitalized, required supplemental oxygen (but not NIV/HFNC)) - the moderately severe category. The response rate was 85% for remdesivir-treated patients with baseline disease point=3 versus 70% response rate for likewise placebo-treated patients on Day 28 (OR=2.38, P=0.0012). On Day 14, the response rate for these patients was 43% for remdesivir versus 33% for placebo (OR=1.53, P=0.0022). For patients with baseline disease point=4 (critically severe category), no similar comparisons were statistically significant. Conclusion and Discussion: The Chinese trial was not really under-powered as previously perceived or portrayed by many opinions. This result supports the preliminary findings of ACTT that remdesivir is effective for patients who were not critically severe. This result also suggests that remdesivir should be given to hospitalized COVID-19 patients as soon as possible. There is no race difference in the treatment effect.